Cancer is an uncontrolled growth and spread of cells that may affect almost any tissue of the body. More than eleven million people are diagnosed with cancer every year. It is estimated that there will be sixteen million new cases every year by 2020. Cancer causes seven million deaths every year worldwide.
Cancer can be defined as abnormal growth of tissues characterized by a loss of cellular differentiation. It is caused due to a deregulation of the signaling pathways involved in cell survival, cell proliferation and cell death.
Current treatments for cancer and related diseases have limited effectiveness and a number of side effects. Cancer therapy currently falls under the following categories including surgery, radiation therapy, chemotherapy, bone marrow transplantation, stem cell transplantation, hormonal therapy, immunotherapy, antiangiogenic therapy, targeted therapy, gene therapy and others.
Activation of phosphatidylinositol-3-kinase (PI3K) results in a disturbance of control of cell growth and survival, and hence this pathway is an attractive target for the development of novel anticancer agents (Nat. Rev. Drug Discov., 2005, 4, 988-1004). The mammalian target of rapamycin (mTOR) regulates cell growth and metabolism in response to environmental cues, hence inhibitors of mTOR may be useful in the treatment of cancer and metabolic disorders (Cell, 2006, 124, 471-484). Hypoxia-inducible factor 1 (HIF-1), a molecular determinant of the response of mammalian cells to hypoxia, has led to the identification of molecular target in the treatment of cancer (Mol. Cancer Res., 2006, 4 (9), 601-605).
PI3K mediated signaling pathway plays a very important role in cancer cell survival, cell proliferation, angiogenesis and metastasis. The PI3K pathway is activated by stimuli such as growth factors, hormones, cytokines, chemokines and hypoxic stress.
Activation of PI3K results in the recruitment and activation of protein kinase B (AKT) to the membrane, which gets phosphorylated at Serine 473 (Ser-473). Thus, phosphorylation of Ser-473 of AKT is a read-out/detector for the activation of the PI3K-mediated pathway. A cell-based ELISA technique can be used to study such activation.
AKT is known to positively regulate cell growth (accumulation of cell mass) by activating the mTOR serine threonine kinase. mTOR serves as a molecular sensor that regulates protein synthesis on the basis of nutrients. mTOR regulates biogenesis by phosphorylating and activating p70S6 kinase (S6K1) which in turn enhances translation of mRNAs that have polypyrimidine tracts. The phosphorylation status of S6K1 is a bonafide read-out of mTOR function.
Most solid tumours have an aberrant PI3K pathway (Nat. Rev. Drug Discov., 2005, 4, 988-1004). Since mTOR lies immediately downstream of PI3K, these tumours also have hyperactive mTOR function.
Hypoxia is defined as loss of oxygen in tissues and is widespread in solid tumors (epithelial or mesenchymal origin) due to the tumors ability to outgrow the existing vasculature.
HIF-1 is master regulator of transcriptional response to oxygen deficiency. It is also upregulated in response to growth factor stimuli. HIF-1 has been implicated in the regulation of genes involved in angiogenesis (e.g. vascular endothelial growth factor (VEG-F), inducible nitric oxide synthase) and anaerobic metabolism (glycolytic enymes).
HIF-1 is a heterodimeric transcription factor consisting of an α (HIF-1α) and a β (HIF-1α) subunit, and is an important regulator of the growing tumor's response to hypoxia. The HIF-1α subunit is degraded rapidly in normoxic conditions and stabilized under hypoxic conditions, while HIF-1α is constitutively expressed. In general, the availability and activity of HIF-1α protein determines the bioactivity of HIF-1 (Current Drug Targets, 2006, 7, 355-369).
Over expression of HIF-1α protein has been demonstrated in many cancers and their metastasis. HIF-1α activates genes that allow the cancer cell to survive and grow in the hostile hypoxic tumor environment. Hypoxic conditions elicit cellular responses designed to improve cell oxygenation/survival through several mechanisms such as neoangiogenesis promotion, improved glycolytic flux enhancing energy production, and up regulation of molecules related to cell survival/apoptosis. Increased tumor HIF-1α has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis, leading to the current interest in HIF-1α as a cancer drug target.
Various approaches have been used to inhibit HIF-1α gene transcription: through antisense strategies, through inhibition of the ability of HIF-1α to interact with proteins that modulate its activity, or through inhibition of the signal transduction pathway. The use of antisense HIF-1α is experimentally relevant in cell culture, but would be difficult to use clinically with current technology (Gene Ther., 2001, 8, 638-645).
HIF-1α is also associated with tumor progression (Cancer Res., 2002, 62, 4316-4324). In addition, over expression of HIF-1α has been demonstrated in many common human cancers such as pancreatic carcinoma, lung carcinoma, colorectal carcinoma, glioblastoma and many other types of cancers. (Cancer Res., 1999, 59, 5830-5835).
Thus, most of the cancer types will potentially benefit from molecules that target one or more of PI3K, mTOR and HIF-1α pathways.
Inflammation is the response of a tissue to injury that may be caused by invading parasites, ischemia, antigen-antibody reactions or other forms of physical or chemical injury. It is characterized by increased blood flow to the tissue, causing pyrexia, redness, swelling, and pain. Each stimulus elicits a characteristic response that has a common theme. Inflammation occurs in three distinct phases:                1. an acute transient phase characterized by local vasodilation and increased capillary permeability;        2. a subacute phase characterized by infiltration of the site by leucocytes and phagocytic cells; and        3. a chronic proliferative phase characterized by tissue degeneration and fibrosis. The recruitment of inflammatory cells to sites of injury involves the concerted interactions of several types of mediators.        
Several cytokines, especially interleukin (e.g. IL-1, IL-6, IL-8) and tumor necrosis factor-α (TNF-α) play an important role in the inflammatory process. Both IL-1 and TNF-α are derived from mononuclear cells and macrophages and in turn induce the expression of a variety of genes that contribute to the inflammatory process. An increase in TNF-α synthesis/release is a common phenomenon during the inflammatory process. Inflammation is an inherent part of various disease states like rheumatoid arthritis, Crohn's disease, septic shock syndrome, atherosclerosis, among other clinical conditions.
PI3K regulates a vast number of signaling pathways (controlling adhesion, migration and phagocytosis) that are crucial in leukocyte function. Specifically, a deficiency of PI3Kγ leads to suppression of in vitro and in vivo recruitment of neutrophils and macrophages to the sites of inflammation. Moreover, it also leads to impaired neutrophil oxidative burst, dendritic-cell migration, as well as impaired T-cell activation in response to inflammatory stimuli (Nat Rev. Immunol., 2007, 7, 191-201). One of the major responses of macrophages to lipopolysacharide (LPS) is to produce TNF-α. TNF-α in turn binds to its specific receptors on leukocytes and mediates the secretion of various cytokines IL-6, IL-8, and the like. It has been reported in literature that TNF activates the PI3K-AKT cascade, which in turn leads to the activation of nuclear factor (NF-κB) (Nature, 1999, 401, 82-85). Thus, inhibiting the PI3K-AKT pathway may have therapeutic potential as anti-inflammatory agents.
LPS from gram-negative bacteria plays a decisive role in initiating pro-inflammatory responses via macrophages. LPS stimulation of macrophages leads to the phosphorylation and activation of p70S6K1 (J. Immunol., 2007, 178, 2542-2548) as well as that of 4EBP1/PHAS-1 (J. Surg. Res., 2001, 97, 54-59); both proteins are bonafide targets of mTOR. Moreover, the PI3K-mTOR pathway regulates the production of nitric oxide (J. Surg. Res., 2001, 97, 54-59) and activates STAT1-dependent transcription (J. Biol. Chem., 2003, 278, 33637-33644) in macrophages in response to LPS.
PI3K is also known to be involved in neutrophil chemotaxis (Eur. J. Pharmacol, 2006, 534, 1-11) and in the pathology of inflammation and rheumatoid arthritis (Nat. Rev. Immunol., 2007, 7, 191-201). As such, it is being considered as an important target for treating both acute and chronic inflammation. Recently, PI3K has been implicated in allergic responses and as a target for treating allergic shocks (FASEB Journal, 2006, 20, 455-456; Nature, 2004, 431, 1007-1011). HIF-1α also plays an important role in myeloid cell activation in response to inflammatory stimuli. It has been reported that HIF-1α activity is increased during the differentiation of monocytes to macrophages. This was also associated with an increase in phosphorylation, activation of p70S6 kinase and inhibition of 4EBP1 thus indicating an involvement of mTOR as well (Am. J. Physiol. Cell Physiol., 2006, 291, C104-113). Thus, targeting HIF-1α may interfere with the functioning of macrophages and thereby alleviate the inflammatory response.
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The present inventors have synthesized and screened molecules which have inhibitory activity towards PI3K and/or mTOR and/or HIF-1α. More importantly, the present inventors have designed and synthesized compounds that target one or more of PI3K, mTOR and HIF-1α pathways.